Various publications, including patents, published applications and technical articles are cited throughout the specification. Each of these cited publications is incorporated by reference herein, in its entirety.
Lung disease, both chronic and acute, remains a significant cause of morbidity and mortality throughout the world. Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death in the world (Spurzem and Rennard, Semin Respir Crit Care Med, 2005; 26: 142-153) and can be caused by anatomic narrowing of the airways or blocking of airways with mucus that interferes with normal breathing. Additionally, interstitial lung disease, also known as pulmonary fibrosis, is classified as a restrictive disease that includes a variety of chronic lung disorders. Management of chronic lung disease includes drug therapy, oxygen therapy, surgery, and pulmonary rehabilitation.
While 90% of COPD patients are smokers, only 10% of smokers develop the disease, suggesting that genetic predisposition may be an important prognostic factor. (Siafakas and Tzortzaki, Respir Med, 2002 August; 96(8): 615-24). Smoker's lung disease is characterized by chronic active inflammation, airway mucus hypersecretion, and emphysema (MacNee, Proc Am Thorac Soc., 2005; 2(4): 258-66; discussion 290-1) and is only partially reversible upon cessation of smoking (Spurzem and Rennard, Semin Respir Crit Care Med, 2005; 26: 142-153). Inflammation of the airways and lung parenchyma plays a major role in the pathogenesis of chronic obstructive pulmonary disease. Cigarette smoke has been shown to induce pulmonary inflammation and ultimately lead to COPD even if exposure to the cigarette smoke has stopped.
Emphysema is one of the major factors determining morbidity and mortality in chronic obstructive pulmonary diseases. This disease is characterized, for example, by loss of elasticity of the lung tissue, from destruction of structures supporting the lung tissues such as alveoli, and destruction of capillaries feeding the alveoli. This destruction can be caused by inflammatory enzymes, for example elastin. Emphysema is defined as the enlargement of peripheral air space in the lung (including respiratory bronchioles and alveoli), which is accompanied by the destruction of alveolar wall structures. The incidence of patients with emphysema has increased in the past decades as a result of the increase in environmental pollutants, cigarette smoking, and other exposure to noxious substances. The current standard of care today demonstrates that only lung transplantation can provide remediation for severe emphysema. There remains a need for an adequate and useful approach to treat, repair and/or ameliorate lung damage in patients with emphysema, such as elastase-induced emphysema.
Animal models exposed to cigarette smoke have been studied to investigate the pathology and the efficacy of various therapeutic interventions. Unfortunately, these studies have only demonstrated limited success. Part of the problem is that commonly used rat and mouse strains show only mild inflammation and mucus secretion in response to cigarette smoke. (Guerassimov, A, et al., Am J Respir Crit Med, 2004 Nov. 1; 170(9): 974-80. Epub 2004 Jul. 28). and the corresponding injuries are rapidly reversible. Healthy laboratory rodents may therefore possess an extraordinary ability to compensate and regenerate lung function following an injury, which may underlie their relative resistance to developing COPD. It has recently been shown that the genetically predisposed spontaneous hypersensitive (SH) rats display phenotypes (e.g., systemic inflammation, hypercoagulation, oxidative stress, and suppressed immune function) that are also found in COPD patients. (Yu, B, et al., Inhal Toxicol, 2008 May; 20(7): 623-33). Therefore, the SH rat model may offer a more relevant model of experimental COPD.
Restrictive lung disease is one of the most common causes of morbidity and mortality and has three primary etiologies, lung cancer, pneumonia and pulmonary fibrosis. Idiopathic pulmonary fibrosis (IPF) is a crippling disease characterized by progressive dyspnea and is associated with a high mortality rate, progressive fixed tissue fibrosis, architectural distortion, and loss of function. (Ortiz, L A, et al., Proc Natl Acad Sci USA., 2003 Jul. 8, 2003; 100(14):8407-11. Epub 2003 Jun. 18). An excess of profibrotic cytokines or a deficiency in antifibrotic cytokines has been implicated in the pathologic process. In the United States, prevalence estimates for idiopathic pulmonary fibrosis vary from three to six cases per one hundred thousand people. Presently, no effective therapies to reverse or retard the course of the disease are available. Most treatments, such as corticosteroids, immunosuppressive, immunomodulatory, or antifibrotic agents, seek to suppress inflammation, but none has been proven to alter IPF disease progression. Therefore, a significant need exists for the development of novel therapies aimed at slowing or halting fibrosis while enhancing endogenous lung repair and regeneration.
It has been shown that mesenchymal stem cells (MSCs) can differentiate into alveolar epithelial cells in injured lungs of mice injured with bleomycin (BLM), and the engraftment of MSCs may suppress inflammation and deposition of collagen in damaged lung tissue. (Zhao, F, et al., Transplant Proceedings, 2008 June; 40(5):1700-1705; Ortiz, L A, et al., Proc Natl Acad Sci USA., 2003 Jul. 8, 2003; 100(14):8407-11, Epub 2003 Jun. 18; Rojas et al., Am J Respir Cell Mol Biol, 2005; 33:145). BLM is a cytostatic antibiotic with antitumor activity and is a well-recognized compound to study pulmonary fibrosis in animal models. It induces alveolar epithelial cell injury and inflammation in the lung, leading to pulmonary fibrosis.
Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) also continue to be significant causes of morbidity and mortality in the intensive care setting. ALI and ARDS are serious diseases characterized by the abrupt onset of hypoxemia with diffuse pulmonary edema in response to either direct injury (e.g., drowning, pneumonia, inhaled toxic gases, and pulmonary contusion) or indirect injury (e.g., severe sepsis, transfusion, shock, and pancreatitis). ALI and ARDS are currently treated by mechanical ventilation and supportive care.
Cell therapy is one of the most exciting fields in translational medicine and is developing into a new therapeutic platform to treat a vast array of clinical disorders. Over the past five years, the field of cell therapies in lung diseases has continued to grow rapidly. Several studies have demonstrated the feasibility of employing cell therapy to treat lung disease. For example, circulating endothelial progenitor cells (EPCs) may contribute to regeneration of diseased pulmonary vasculature and are being investigated in patients with pulmonary hypertension. (Diller, G P, et al., Circulation, 2008 Jun. 10, 117(23): 3020-30, EPub 2008 Jun. 2). In addition, recent publications demonstrate that mesenchymal stem cells (MSCs) also suppress lung injury and inflammation in several mouse models of inflammatory and immune-mediated lung diseases. (Weiss, D J, et al., Proc Am Thorac. Soc., 2008 Jul. 15; 5(5):637-67). Despite these promising findings, little attention has been placed on the development of a cell therapy for ALI.
Presently, there is interest in using either stem cells, which can divide and differentiate, or muscles cells from other sources, including smooth and skeletal muscles cells, to assist in the repair or reversal of tissue damage, such as lung damage due to lung diseases, disorders or injury. Transplantation of stem cells can be utilized as a clinical tool for reconstituting a target tissue, thereby restoring physiologic and anatomic functionality. The application of stem cell technology is wide-ranging, including tissue engineering, gene therapy delivery, and cell therapeutics, i.e., delivery of biotherapeutic agents to a target location via exogenously supplied living cells or cellular components that produce or contain those agents. The identification of stem cells has stimulated research aimed at the selective generation of specific cell types for regenerative medicine.
A reliable, well-characterized and plentiful supply of substantially homogenous populations of such cells having the ability to differentiate into an array of lung tissue, including vascular structures, would be an advantage in a variety of diagnostic and therapeutic applications for lung repair, regeneration, protection and improvement, and for improvement of blood flow and oxygen/CO2 exchange before, during or subsequent to lung damage due to lung diseases, disorders, and/or injuries.